This is a request for a renewal of a Senior Scientist Award that will allow me to continue to acquire molecular genetic and neuroscience techniques and to use them to achieve the goals of two NIDA funded research projects. Both projects are designed to test the hypothesis that glutamatergic receptors composed of NR1 or GluR2 subunits are necessary for the neuronal plasticity that is manifest as injury-induced pain (nociception) and the adaptations that occur during repeated cocaine or opioid use and are manifest as drug reward and relapse as well as opioid tolerance and dependence. The first project will use the spatial-temporal knockout (KO) that we have developed to determine the role of spinal cord dorsal horn of NMDAR1 (NMDA receptor) and/or GluR2 (AMPA receptor) subunits in persistent pain resulting from inflammation and spinal nerve injury. The second project will use this same Cre-loxP technology to produce a KO of the NMDA and AMPA receptors that is confined to selected supraspinal CNS areas including the nucleus accumbens, ventral tegmental area and ventral subiculum (a spatial KO) in adult mice (a temporal KO). We will demonstrate by immunocytochemical, in situ hybridization and electron microscopy techniques, the spatial localization and temporal characteristics of the changes in gene expression that are associated with the deletion of the target receptor subunits. We will also determine whether the targeted deletion of these receptor subunits in the selected CNS areas given above will attenuate glutamatergic currents and decrease or prevent the behavioral adaptations to cocaine and opioid use including drug reward and relapse and opioid tolerance and dependence. The acquisition and application of these techniques will be accomplished through collaborative arrangements and through the utilization of institutional core facilities that complement the expertise available in my laboratory. This SSA award will also allow me to continue the reduction in teaching and administrative responsibilities that has significantly increased the time I was able to devote to enhancing my scientific skills.